Prof. Aharon Friedman

Research Interests

The overall goal of our past and present research activities is to understand cellular and molecular mechanisms governing the interaction between the gastrointestinal tract and the immune response. Interactions between the immune response and the gastrointestinal tract may occur at several levels, three of which have become the focus of our investigations:

Development of the gut-associated immune system (GALT) in omnivorous birds: influences of gastro-intestinal development, bacterial colonization and nutrition.
Immune related function s of the intestinal epithelial cell (IEC)
Development of tolerance or response following intestinal (oral or rectal) intake of antigen.

Effects of gastro-intestinal development on mucosal immune competence

Many omnivorous birds begin foraging immediately after hatch. This means that they become immediately exposed to adult-type food and environmental bacteria at a time where the intestinal tract is still tuned to an embryonic environment. Hence, to survive, the digestive tract of these birds must undergo rapid development in terms of digestive and protective capacities. The goals of our research are directed towards describing the mechanism by which GALT undergoes this rapid development, and how it protects the hatchling from succumbing at an early age to environmental pathogens. To investigate the development of the avian GALT we have developed numerous tools that allow investigation of GALT development at the level of the gene, protein and cell.

Several of our major findings are:

Adaptive immunity in the avian GALT becomes fully functional (only) during the second week of life.
Innate immune systems and maternal antibodies protect chicks during the first week of life.
Impaired gut development leads to delayed maturation of GALT.
Bacterial colonization has significant impact on development of GALT in the hindgut.

Immune-related functions of the avian IEC

The IEC has a central role in digestion and absorption functions in the gut. In the mammal, it is now widely accepted that the IEC functions as an immune sentinel with signaling properties. These properties include cognitive interactions with neighboring immune cells (i.e. dendritic cells, NKT cells and many more), and may include transfer of IEC stress during pathogen attack. The avian IEC has to date been shown include very few immune response properties. This deficiency in knowledge is due mainly to difficulties in culturing avian IEC in vitro. We have, for some time now, made attempts to culture IEC with little success; recently, however, we have managed to decipher some of the requirements of these cells, and are now proceeding to a more detailed analysis of immune-related functions of the avian IEC.

Several of our major observations are:

Avian IEC are extremely fragile in culture, but with the correct conditions may be cultured for at least 36 hours and for as long as 15 days.
Toll like receptors are constitutively expressed by these cells, and they can be selectively induced to up- or down-regulate these receptors.
Avian IEC respond very well to bacterial LPS.
Avian IEC express the poly-Ig-receptor for IgA

Tolerance or response following intestinal exposure to antigen

Oral vaccines provide a major means to vaccinate large populations at a low cost. This approach is of particular interest to the poultry industry in which major vaccination programs include the inoculation of individual chicks in flocks containing over 100,000 birds. One of the main issues in development of intestinal vaccines is to be able to predict the immunogenicity and consequential protection of the designed vaccine. The immunological properties of the vaccine depend on the structure of the vaccine itself and on the interaction between the immunogen and the intestinal immune system. A given protein antigen can be either immunogenic or tolerogenic depending on the circumstances it is encountered by the immune system. Thus, protein antigens administered orally can frequently induce immune tolerance (oral tolerance), while if administered by parenteral injection – they will induce robust immun responses. Hence, with the aim of developing potent oral-vaccination strategies, we are interested in investigating mechanisms responsible for oral tolerance, and in developing strategies for oral immunization - and particularly so in poultry. Again, the entire research program focused on the quest to develop efficient oral vaccines for poultry.

Several of our major findings are:

We were the first to publish that clonal anergy is a mechanism for oral tolerance.
Oral tolerance can be demonstrated for both Th1 and Th2 phenotypes.
The co-stimulatory molecule CTLA-4 is involved in generation of peripheral tolerance.
Birds are surprisingly different from mammals in that oral antigen usually leads to response rather than tolerance.
Oral tolerance may be induced in very young chicks with immature intestinal systems.

Aharon Friedman

Curriculum Vitae

Professor of Immunology

Ron Barbaro Chair in Veterinary Medicine

Education

B.Sc. Animal Sciences, Hebrew University, 1976
M.Sc. Immunology, Hebrew University, 1978
Ph.D. Immunology, Weizmann Institute of Science, 1983

Postdoctoral Research

Rothschild's Fellow, Harvard Medical School, 1983

Biographical Sketch

Ronnie Friedman was born in Johannesburg South Africa on June 9, 1951. He received his undergraduate and Masters training at the Hebrew University of Jerusalem, and his Ph.D., researched under the supervision of Professor Irun Cohen, was received from the Weizmann Institute of Science. He then spent 2 years as a postdoctoral fellow with Professor Emil. R. Unanue at the Harvard Medical School, Boston. He was appointed Lecturer in Animal Sciences in the Faculty of Agricultural, Food and Environmental Sciences, the Hebrew University of Jerusalem in 1986. He is now Professor of Immunology and holds the Ron Barabaro Chair in Veterinary Medicine.

Aharon Friedman

List of Publications

Several Key Publications

Weiner, H.L., Friedman, A., Miller, A., Khoury, S.J., Al-Sabbagh, A., Santos, L.M.B., Sayegh, M., Nussenblatt, R., Trentham, D.E . and Hafler, D.A.
Oral tolerance: immunologic mechanisms and treatment of murine and human organ specific autoimmune diseases by oral administration of autoantigens. Annu. Rev. Immunol. 1994; 12: 809-838.
Friedman, A. Induction of anergy in Th1 lymphocytes by oral tolerance. Ann. NY Acad. Sci. 1996; 103-110.
Friedman, A. , Bar Shira, E. & Sklan, D. Ontogeny of gut associated immune competence in the chick. World Poultry Sci. J. 2003; 59:209-219.
Friedman, A. and Weiner, H.L. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc. Natl. Acad. Sci. USA 1994; 91:6688-6692.
Halevy, O., Arazi, Y., Melamed, D., Friedman, A. and Sklan, D. Retinoic acid receptor-α is modulated by dietary vitamin A and by retinoic acid in chick T lymphocytes. J. Nutr.1994; 124:2139-2146.
Melamed, D., Fishman-Lobell, J., Uni, Z., Weiner, H.L. & Friedman, A. Peripheral tolerance in Th2 lymphocytes following continuous oral exposure to antigen. Int. Immunol. 1996; 8:717-724.
Klipper, E., Sklan, & Friedman, A. Immune responses of chickens to dietary protein antigens: I. Induction of systemic and intestinal immune responses following oral administration of soluble proteins in the absence of adjuvant. Vet. Immunol. Immunopathol. 2000; 74:209-223.
Bar Shira, E. Sklan, D. & Friedman, A. Establishment of immune competence in the avian GALT during the immediate post-hatch period. Develop. Comp. Immunol. 2003; 27:147 – 157.
Klipper, E., Sklan, D & Friedman, A. Maternal antibodies block induction of peripheral tolerance in newly hatched chicks. Vaccine 2004; 22:493-504.
Bar Shira, E., Sklan, D. & Friedman A. Impaired immune responses in hatchling hindgut following delayed access to feed. Vet. Immunol. Immunopathol. 2005; 105:33-45.

Aharon Friedman

Lab members

The Group

Enav Bar Shira, PhD : Lab manager and project coordinator

Ph.D. Students

Inbal Bromberger. Expression and characterization of Ig transporters in the chick cloacal bursa and gut.

M.Sc. Students

Neta Netzer-Cohen: Selection of B lymphocyte repertoire by bacterial products in the cloacal bursa (LPS and CpG).

Ori Elad: Transfer of maternal IgA from the egg to the avian embryonic gut and its uptake by goblet cells.

Aharon Friedman

Alumni

Alumni (partial list)

Doron Melamed, PhD - Rappaport Institute, Technion

Yaakov Waksman, PhD

Avner Adini, PhD

Shay Weiss, PhD

Ran Zichel, PhD

Helena Yagev, PhD

Eyal Klipper, PhD

Assaf Adlershtein

Vets and Vets to be...

Liron Hirsch

Raaya Ilia

Shirly Cohen

Ana Dorfman

Aharon Friedman

Teaching

Courses and Teaching

at the Faculty of Agriculture, Food and Enviroment
and the Koret School for Veterinary Medicine

Undergraduate Courses

Introduction to Cell Biology ( 71079: 2 credits):
A compulsory course for first-year students in animal and food sciences. A weekly 2 hour lecture covers the general aspects of mordern cell biology.

Basic histology ( 71802: 4 credits; 65739: 4 credits):
Basic histology is compulsory for students of animal sciences, and is given during their first year (spring semester). The course is composed of 1 hour lecture and 3 hours laboratory per week, and covers the histology of all tissues.

Organ histology ( 71820: 1.5 credits ):
Organ histology is compulsory for students of animal sciences, and is given during their second year (fall semester). The course includes 3 hours laboratory every two weeks, and includes the histological structures of all major organs.

Basic physiology of domestic animals ( 71801: 7.5 credits):
The course is compulsory for students of animal sciences, and is given during their second year (fall semester). The course is composed of 6 hour weekly lectures and 3 hour bi-weekly labs. Basic physiology covers basic physiological processes and emphasizes physiological regulation at the level of the whole animal.

Basic Immunology ( 71811: 3 credits):
This course is compulsory for students of animal sciences, and is open for participation of all undergraduates in the faculty; it is given during the spring semester, and includes 3 hour weekly lectures. Topics covered include general aspects of cellular and molecular immunology.

Laboratory in Immunology ( 71209: 1.5 credits):
Laboratory for students in the biotechnology program. Production, purification and evaluation of antibodies from egg yolk.

Graduate Courses

Advanced Immunology ( 71914: 3 credits):
An advanced course including lectures and seminar sessions that provides an in depth understanding of the cellular, genetic and molecular basis of modern immunology.

Clinical Immunology ( 65710: 3 credits):
An advanced course on the pathology of the immune system.

Laboratory in Hematology ( 73514: 2 credits)
Main laboratory procedures in hematology, with emphasis on the cell assays.

Laboratory in Immunology ( 71984: 2 credits):
Main laboratory procedures in immunology

Aharon Friedman

Custom Made Antibodies

As experienced chicken immunologists, we make extensive use of chicken antibodies purified from egg yolks and bile. We have perfected the methods for purifying IgY from yolk and chIgA from bile, and have recently begun to provide custom made antibodies to many of our colleagues that were unable to produce or purchase antibodies that matched their demands. We provide highly specific and purified antibodies at a cost that covers our expenses and that enables us to maintain our layer colony.

For further details please contact Prof. Friedman.

Aharon Friedman